The long-term objective of my laboratory is to understand the role of cell adhesion molecules in learning and memory, with an emphasis on integrins. Drosophila is an excellent model system for such investigations because of its powerful genetics and ability to perform well in many memory paradigms. Additionally, since the molecular events involved in learning and memory are well conserved from flies to mice, studies utilizing Drosophila will continue to provide highly relevant information regarding the fundamental molecular events underlying behavioral plasticity. Previously, a new Drosophila olfactory memory mutant called Volado was isolated. The Volado fly carries a mutation in a novel integrin alpha subunit gene. Integrins have not been widely studied for their role in learning and memory; however, they have been examined in a number of other processes. For example, integrins mediate cell-cell as well as cell-substrate adhesion, and have important roles in development, tumor metastasis and wound healing. While the signaling properties of integrins have also been explored extensively, only a small number of proteins that bind to the cytoplasmic regions of integrins have been identified. Thus, there is a large gap in our understanding of integrin-mediated processes underlying memory as well as integrin-mediated protein-protein interactions in general. One of the major goals during this funding period will be to identify the requisite integrin beta subunit that physically interacts with the Volado gene product. This will be accomplished by analyzing olfactory memory in animals harboring mutations in candidate beta subunit genes, determining whether the beta subunit is active in the adult or participates in developmental processes important for olfactory memory, and exploring genetic and biochemical links between Volado and its beta subunit. Another major goal will be to delineate the brain regions in which Volado and the beta subunit are active using targeted gene expression strategies in combination with behavioral analyses. Additionally, the role of proteins that directly bind to the cytoplasmic domains of Volado and its beta subunit will be explored via molecular and biochemical studies. Collectively, these studies will identify the integrin beta subunit that associates with the Volado gene product, determine where these two proteins must be expressed for normal memory to occur, and identify candidate proteins that function downstream of integrins in behavioral plasticity. Thus, the proposed studies will add greatly to our understanding of the molecular and cellular processes mediated by integrins within the context of learning and memory.